EP0874621B1 - [3'-DESOXY-3-OXO-MeBmT]1-[Val]2-CICLOSPORIN-CONTAINING EMULSION PHARMACEUTICAL COMPOSITIONS - Google Patents

[3'-DESOXY-3-OXO-MeBmT]1-[Val]2-CICLOSPORIN-CONTAINING EMULSION PHARMACEUTICAL COMPOSITIONS Download PDF

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Publication number
EP0874621B1
EP0874621B1 EP97901563A EP97901563A EP0874621B1 EP 0874621 B1 EP0874621 B1 EP 0874621B1 EP 97901563 A EP97901563 A EP 97901563A EP 97901563 A EP97901563 A EP 97901563A EP 0874621 B1 EP0874621 B1 EP 0874621B1
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Prior art keywords
emulsion
concentrate
fat
active agent
fat emulsion
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EP97901563A
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German (de)
English (en)
French (fr)
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EP0874621A1 (en
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Harry Tiemessen
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Novartis Pharma GmbH
Novartis AG
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Novartis Pharma GmbH
Novartis AG
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Priority to EP05018663A priority Critical patent/EP1679064B1/en
Priority to EP02022256A priority patent/EP1273288B1/en
Priority to EP02022257A priority patent/EP1273289B1/en
Priority to DK02022256T priority patent/DK1273288T3/da
Priority to DK02022257T priority patent/DK1273289T3/da
Publication of EP0874621A1 publication Critical patent/EP0874621A1/en
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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Definitions

  • PCT application publication no. WO 93/20833 discloses surfactant-containing compositions of [3'-desoxy-3'-oxo-MeBmt] 1 -[Val] 2 -Ciclosporin in which Cremophor (a polyethylene glycol-hydrogenated castor oil) is a preferred surfactant.
  • Cremophor a polyethylene glycol-hydrogenated castor oil
  • this invention provides a concentrate for intravenous administration of an emulsion comprising
  • the mean fat droplet size is between about 250nm to 500nm. Solid material having a dimension e.g. diameter > 200 nm, e.g. undissolved drug compound (active agent) is collected and retained by the filter pores. The fat droplets are flexible, however, and pass through the filter pores.
  • the mean diameter of the droplets in the fat emulsion compositions of this invention is substantially similar to the droplet diameter in the placebo emulsion.
  • a "Nucleopore" filter is an example of a high-quality filter available commercially.
  • a “pharmaceutical emulsion” is understood herein as a composition in which the individual components or ingredients are themselves pharmaceutically acceptable and, when a particular form of administration is foreseen, are suitable or acceptable for that form of administration.
  • the emulsion contains 1-30, preferably 8 to 20, particularly 10 to 20 and especially 10 to 16 percent by weight of fat.
  • cyclosporins are insoluble in an aqueous medium, they are typically dissolved in a mixture of alcohol and poly(oxyethylene)-40-castor oil in order to enable intravenous administration, and just before use diluted with brine or a glucose solution and slowly infused.
  • cyclosporin A is merely available as a concentrate (Sandimmune R - infusion - concentrate) with alcohol and poly(oxyethylene)-40-castor oil, which are not ideal excipients.
  • Poly(oxyethlyene)-40-castor oil in injection and infusion solutions may lead to hypersensitivity reactions especially in people with allergic symptoms or in people, who shortly before have had a comparable composition with the same excipient by injection or infusion. Hypersensitivity reactions may include lowering of blood pressure, deficient blood circulation or lack of air. On longer-term use an increase of blood fat values with pathological shift of lipoprotein profile, prejudiced flowing properties of the blood and increased aggregation readiness may occur.
  • Poly(oxyethlyene)-40-castor oil, e.g. Cremophor R EL -, a non-ionic emulsifier is not a natural oil and is - in contradiction to them - soluble in water.
  • a cyclosporin concentrate is described, which is a sterile solution of cyclosporin in a mixture of alcohol and a plant-oil. This composition however is not suitable for injection, since the injection of an oil in this concentrated form may cause a lethal embolism.
  • cyclosporins are soluble in natural oils, it would be obvious to dissolve them simply in fat emulsions available commercially, e.g. in Intralipid R , by addition of crystalline cyclosporin. This however is not realisable, since even after intensive stirring, a predominating amount remains present in the form of undissolved crystals.
  • a loading up of the fat droplets in the aqueous fat emulsion is hardly possible and the final result is an emulsion having an amount of cyclosporin dissolved which is insufficient for a therapeutically suitable effect and additionally contains solid cyclosporin crystal particles which may be of a dangerously large size for intravenous injection or infusion.
  • fatty acid chains preferably 40-60, more preferably 45-55% by weight is unsaturated.
  • a particularly suitable fat is soybean oil.
  • Ready made fat emulsions, suitable as a component for the fat emulsion of the invention include commercially available products like Lipofundin 10% MCT, or Intralipid of Kabi, or Abbolipid.
  • Lipofundin MCT contains as an oil phase a 1:1 mixture of long chain triglycerides (LCT) and medium chain triglycerides (MCT, Miglyol 810 or 812, preponderantly consisting of caprylic /capric triglyceride), This mixture leads to a faster uptake of the fat droplets in the blood stream, thereby avoiding an impairment of the immune system of the liver function.
  • the half-life of LCT/MCT in the blood is between 10 and 30 minutes.
  • the fast elimination of the lipid carrier avoids its accumulation in the blood and is therefore expected to have no or minimal influence on the elimination kinetics of the drug compound during a prolonged infusion.
  • the MCT/LCT mixture may have better solubilsation properties than LCT alone.
  • the drug-loaded fat emulsion of this invention further contains a stabiliser preferably a phospholipid or such one having a (C 12-22 )-1-alkylether or -1- ⁇ , ⁇ -alkenyl-ether group in position 1 (see for such special structures: Karlson, Doenecke and Koolman, Kurzes Lehrbuch der Biochemie fürtechnik fürtechnik, 1994, page 306, figure 13.2, a plasmanyl - or plasmenylethanol amine).
  • a stabiliser preferably a phospholipid or such one having a (C 12-22 )-1-alkylether or -1- ⁇ , ⁇ -alkenyl-ether group in position 1 (see for such special structures: Karlson, Doenecke and Koolman, Kurzes Lehrbuch der Biochemie fürtechnik, 1994, page 306, figure 13.2, a plasmanyl - or plasmenylethanol amine).
  • a glycolipid (see also Karlson, page 289, the table and page 303), a compound with a mono- or oligosaccharide moiety instead of a phosphate variety, especially a sphingolipid (page 303, 308), e.g. sphingomyelin (page 308, 309) is also contemplated as stabiliser.
  • a phospholipid which is negatively charged
  • a diacylphosphatidyl glycerol especially such one having an unsaturated (C 12-22 ) fatty acid moiety, e.g. palmitoyl oleoyl phosphatidylglycerol (hereafter POPG), egg-phosphatidylglycerol, soy-phosphatidylglycerol, or diacyl-phosphatidylglycerol, or a salt thereof, e.g. sodium-, potassium- or ammonium-POPG, more preferably NaPOPG.
  • POPG palmitoyl oleoyl phosphatidylglycerol
  • POPG palmitoyl oleoyl phosphatidylglycerol
  • egg-phosphatidylglycerol soy-phosphatidylglycerol
  • diacyl-phosphatidylglycerol or a salt thereof, e.g. sodium-,
  • Another preferred stabiliser is a saturated, mono- or di-unsaturated (C 12-24 ) fatty acid, especially oleic acid, or a salt thereof e.g. sodium, potassium or ammonium oleate, more preferably sodium oleate.
  • the stabiliser used in the present invention serves to increase the concentration of active agent in the ready-to-use fat emulsion, and to increase the rate of formation of the emulsion.
  • the active agent is incorporated stably and rapidly within the fat droplets of the placebo fat emulsion.
  • the ready-to-use emulsion may be formed rapidly, e.g. in less than or about 1 second or in a few seconds.
  • the stabiliser in the compositions of this invention provides at least a two-fold, e.g. a three-fold, four-fold, five-fold or higher multiple increase of solubilisation of active agent in fat droplets of the placebo fat emulsion when compared with a simple mixture of active agent with placebo fat emulsion.
  • a concentration of at least about 5 mg PSC 833 per ml fat emulsion and up to about 20 mg/ml may be obtained.
  • a concentration of active agent of at least about 3 mmol/litre fat emulsion e.g. 4 mmol/litre, 5 mmol/litre or more and up to about 20 mmol/litre may be obtained.
  • the drug compound containing fat emulsion additionally contains, for a larger drug compound load, an organic solvent, e.g. polyethylene glycol, e.g. polyethylene glycol 300 or 400.
  • organic solvent e.g. polyethylene glycol, e.g. polyethylene glycol 300 or 400.
  • Ethanol and propylene glycol are also possible, e.g. in a 1:99 to 99:1 weight mixture, e.g. 25:75 to 75:25, and preferably a mixture of about 45:55 to 55:45, e.g. a 50:50 weight mixture of ethanol and propylene glycol is used, thereby recognising the good dissolving efficacy of ethanol and the undesirahility of a greater alcohol concentration in the blood after administration of the emulsion.
  • Tthis invention provides a pharmaceutical concentrate containing [3'-desoxy-3'-oxo-MeBmt] 1 -[Val] 2 -Ciclosporin and a stabiliser in a weight ratio of [3'-desoxy-3'-oxo-MeBmt] 1 -[Val] 2 -Ciclosporin to stabiliser of from 400:1 to 10:1, e.g. 200:1, more preferably from 100:1 to 10:1, e.g. 50:1, 40:1, 30:1, 20:1 or 10:1, as a component for the fat emulsion of the invention.
  • a product of about the same formation is generally known from UK Patent GB 2 269 536 B, but not as a starting product for incorporating into a fat emulsion.
  • product disclosed in GB 2 269 536 through a 200 nm pore filter, all product containing active agent, e.g. peptide, is retained on the filter.
  • the concentrate of this invention is present in an organic solvent in an amount of up to 20%, e.g. 0.1 to 20% by weight of the drug compound related to the concentrate weight, which solvent makes the concentrate at least intravenously applicable.
  • the stabiliser in the concentrate of this invention may be the phospholipid, the glycolipid or the fatty acid, if present, in the placebo fat emulsion.
  • the drug containing fat emulsion is prepared by mixing, preferably by injecting, the concentrate, whether in liquid or in solid form, preferably in liquid form (to facilitate the incorporation of the drug compound and stabilizer into the dissolved fat droplets) into the placebo fat emulsion, after which the drug containing fat emulsion, preferably up to 24 hours after its preparation may be administered to a patient.
  • the applicants contemplate oral administration of a concentrate or emulsion of this invention, e.g. in a flavoured drink solution or milk; nasal administration; via inhalation; or topically, e.g. dermally.
  • the exact dosage to be used may be determined in conventional manner, e.g. in standard bioavailability tests in animals, e.g. dogs. In general the dosages are from about 100% to 200% that of known formulations.
  • compositions of this invention are useful for the known indications of [3'-desoxy-3'-oxo-MeBmt] 1 -[Val] 2 -Ciclosporin , e.g. for the following conditions:
  • compositions to be administered depends on several factors, for example the desired duration of treatment and the rate of release of the active ingredient.
  • the utility of the pharmaceutical compositions can be observed in standard clinical tests in, for example, known indications of active agent dosages giving equivalent blood levels of active agent; for example using dosages in the range of 1 mg to 1000 mg, e.g. 5mg to 100mg, of active agent per day for a 75 kilogram adult and in standard animal models.
  • the increased bioavailability of the drug substance provided by the compositions can be observed in standard animal tests and in clinical trials. For example an indicated adult daily dose following renal transplantation is from 50 to 200 mg/day.
  • Example 1 The concentrate of Example 1 may be introduced into Lipofundin R MCT 10%, a placebo fat emulsion, e.g. by injection at a dilution factor of about 17, giving the following composition: mg/ml PSC 833 5.9 Sodium oleate 0.59 Ethanol 24.4 Propylene glycol 23.8 Lipofundin MCT 10% components: MCT/LCT 94.3 Egg phosphatidyl choline 11.3 Glycerol 23.6 Sodium oleate 0.28 107 ml of the PSC 833 containing fat emulsion (obtained from 7 ml of the concentrate and 100 ml of Lipofundin R MCT 10%) is a sufficient dosage for a patient of 70 kg of body weight, leading to a moderate load of 10 g of fat, 2,6 g of ethanol, 2.5 g of propylene glycol and 631 mg of PSC 833 per day, since the necessary dosage by injection is 9 mg PSC 833 per kg of body weight, which is for a patient of
  • a patient of 70 kg of body weight thus needs about 1400 mg PSC 833 for oral use, in a fat emulsion, which may be prepared by mixing of 14 ml of the concentrate of Example 1 with 100 ml or more of Lipofundin R 10% MCT.
  • the required amount of drug solution may be taken from a 5 ml ampoule containing 500 mg of PSC 833 concentrate and/or of a 2.5 mg ampoule containing 250 mg PSC 833 and may be introduced by injection into 100 ml of Lipofundin R MCT 10% whereafter the combined mixture may be administered to a patient by infusion or oral application.
  • compositions 3 to 7 and 8 to 12 are those according to the invention
  • compositions 13a and 13b duration 2 hours or orally (13c). No significant formulation-dependent side effects were observed. Blood concentration is determined by radioimmunoassay (RIA) and results of the three administered compositions are shown graphically in Figure 1.
  • RIA radioimmunoassay
  • the fat emulsion thus may, just as the emulsion described before, contain particles which can not be administered without any potential danger, especially if the emulsion has a larger drug loading concentration.
  • a fat emulsion is available, which has, with a comparable amount of drug compound, an excipient load related to the fat amount, of one tenth of that in hitherto known compositions.
  • the fat emulsion of the art is produced starting from all the different components, which are mixed in a homogenizer under high pressure. Since it is produced in one step, it is comparable with the emulsion of EP 0570829 A1, described before and has the same disadvantage of tending to exhibit precipitation of active ingredient.
  • Amphotericin is transformed into a water soluble complex, with a phosphatidyl glycerol in an acid medium, optionally in the presence of phosphatidyl choline and of cholesterol.
  • the molar ratio is 0.4 parts of Amphotericin: 0.8 parts of distearoyl phosphatidyl glycerol: 2.0 parts of hydrogenated egg phosphatidyl choline: 1.0 parts of cholesterol (see page 7, table and also claim 7).
  • the pH is 4.5.
  • the amounts of excipients are so large that upon addition of an aqueous phase to this pharmaceutical intermediate, liposomes (see page 2, line 5) are formed which incorporate the drug compound.
  • the pH is preferably not in the acid range.
  • liposomes are produced which may be stabilized by lyophilization to guaranteee an adequate shelf life.
  • colloidal particles of the drug compound cyclosporin A which is very poorly soluble in water, together with a stabilizer are prepared in a weight ratio of active substance: stabilizer of 2:1 and with diameters of about 1.0 micrometers and thus lie inside the drug compound: stabilizer weight ratio of the concentrate used as a component for the fat emulsion according to the invention.
  • a solution of the cyclosporin and the stabilizer in absolute ethanol and polyethylene glycol 400 is injected in dextrose containing water leading to a suspension of stabilized colloidal particles and not, as according to the present invention, into a fat emulsion.

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EP97901563A 1996-01-19 1997-01-20 [3'-DESOXY-3-OXO-MeBmT]1-[Val]2-CICLOSPORIN-CONTAINING EMULSION PHARMACEUTICAL COMPOSITIONS Expired - Lifetime EP0874621B1 (en)

Priority Applications (5)

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EP05018663A EP1679064B1 (en) 1996-01-19 1997-01-20 Pharmaceutical compositions containing rapamycin derivatives
EP02022256A EP1273288B1 (en) 1996-01-19 1997-01-20 Pharmaceutical compositions containing rapamycin derivatives
EP02022257A EP1273289B1 (en) 1996-01-19 1997-01-20 Pharmaceutical compositions containing ascomycin derivatives
DK02022256T DK1273288T3 (da) 1996-01-19 1997-01-20 Lægemiddelsammensætning indeholdende rapamycinderivater
DK02022257T DK1273289T3 (da) 1996-01-19 1997-01-20 Farmaceutiske sammensætninger indeholdende ascomycinderivater

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GBGB9601120.0A GB9601120D0 (en) 1996-01-19 1996-01-19 Organic compounds
GB9601120 1996-01-19
PCT/EP1997/000252 WO1997025977A1 (en) 1996-01-19 1997-01-20 Pharmaceutical compositions

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EP02022257A Division EP1273289B1 (en) 1996-01-19 1997-01-20 Pharmaceutical compositions containing ascomycin derivatives
EP02022256A Division EP1273288B1 (en) 1996-01-19 1997-01-20 Pharmaceutical compositions containing rapamycin derivatives

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EP02022257A Expired - Lifetime EP1273289B1 (en) 1996-01-19 1997-01-20 Pharmaceutical compositions containing ascomycin derivatives
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DE69721729T2 (de) 2003-12-11
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JP4077386B2 (ja) 2008-04-16
EP1273289B1 (en) 2005-11-23
AU1543497A (en) 1997-08-11
ATE510532T1 (de) 2011-06-15
DE69734742T2 (de) 2006-07-27
WO1997025977A1 (en) 1997-07-24
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PT874621E (pt) 2003-09-30
DE69734253D1 (de) 2006-02-02
EP1273288B1 (en) 2005-09-21
GB9601120D0 (en) 1996-03-20
US6239102B1 (en) 2001-05-29
CA2240339C (en) 2010-11-16
JP2007246543A (ja) 2007-09-27
DK1273289T3 (da) 2006-03-20
HK1053973A1 (en) 2003-11-14
EP0874621A1 (en) 1998-11-04
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KR100485146B1 (ko) 2005-10-12
ATE304842T1 (de) 2005-10-15
CA2240339A1 (en) 1997-07-24
DK1679064T3 (da) 2011-09-12
KR19990076603A (ko) 1999-10-15
DK1273288T3 (da) 2005-11-21
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HK1054183A1 (en) 2003-11-21
ATE310504T1 (de) 2005-12-15
EP1679064B1 (en) 2011-05-25
DE69734742D1 (de) 2005-12-29
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DK0874621T3 (da) 2003-09-01
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ES2247245T3 (es) 2006-03-01
PT1679064E (pt) 2011-07-25
ATE239449T1 (de) 2003-05-15
DE69734253T2 (de) 2006-07-06
HK1015277A1 (en) 1999-10-15
CA2678707A1 (en) 1997-07-24
DE69721729D1 (de) 2003-06-12
JP2004107350A (ja) 2004-04-08
JP3763581B2 (ja) 2006-04-05
EP1679064A2 (en) 2006-07-12
EP1273289A1 (en) 2003-01-08
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